With over 56,000 new cases diagnosed in the US in 2012 and the incidence on a dramatic rise, thyroid cancer is both common and escalating. Traditional therapies are ineffective against advanced papillary thyroid cancer and anaplastic thyroid cancer. Approximately 45% of papillary thyroid cancers have an activating mutation of the BRAF gene, BRAFV600E. The proposed research will utilize novel engineered murine thyroid cancer cell lines, patient-derived primary human cell lines, and an orthotopic mouse model of thyroid cancer to investigate targeted therapeutics (the BRAFV600E-inhibitor PLX4720 and the Src-inhibitor dasatinib) and analyze the role of Src-FAK signaling in BRAFV600E tumor cell progression and metastasis. Our central hypothesis is that Src-FAK signaling is an important contributing factor to BRAFV600E thyroid cancer progression and that inhibition of the Src-FAK signaling pathway will further sensitize thyroid cancer cells to BRAFV600E-inhibition. This will be the first work to elucidate the role of Src-FAK signaling in the context of BRAFV600E-inhibition. I addition to adding to the current understanding of intracellular signaling pathways that contribute to thyroid cancer tumor progression, this project ultimately aims to determine the potential for combining two targeted therapeutics, currently in clinical trials, for use in advanced thyroid cancer as well as identify biomarkers that will indicate the response to therapy.